Introduction of a benzyl group onto the 2′-OH of 6-chloropurine 3′-O-benzoylriboside

Article abstract of DOI:10.1081/NCN-120022633

A new method to introduce a benzyl group onto the 2′-OH of purine ribonucleoside is described. Thus, 6-chloropurine 3′-O-benzoylriboside and its 5′-O-trityl congener were condensed with benzyl alcohol using the Mitsunobu reaction to give the 2′-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depending on the solvent. The product was converted to adenosine, indicating that the stereochemistry at C-2′ is retained.

Full text of DOI:10.1081/NCN-120022633

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Introduction of a Benzyl Group onto the 2′-OH of 6-
Chloropurine 3′-O-Benzoylriboside
Shigetada Kozai a , Tomoyo Fuzikawa a , Keisuke Harumoto a & Tokumi Maruyama a b
a Faculty of Pharmaceutical Sciences , Tokushima Bunri University , Yamashiro-cho,
Tokushima, Japan
b Faculty of Pharmaceutical Sciences , Tokushima Bunri University , Yamashiro-cho,
770-8514, Tokushima, Japan
Published online: 31 Aug 2006.
To cite this article: Shigetada Kozai , Tomoyo Fuzikawa , Keisuke Harumoto & Tokumi Maruyama (2003) Introduction of a
Benzyl Group onto the 2′-OH of 6-Chloropurine 3′-O-Benzoylriboside, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8,
779-781, DOI: 10.1081/NCN-120022633
To link to this article: http://dx.doi.org/10.1081/NCN-120022633
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 779–781, 2003
Introduction of a Benzyl Group onto the 20-OH
of 6-Chloropurine 30-O-Benzoylriboside
Shigetada Kozai, Tomoyo Fuzikawa, Keisuke Harumoto,
*
and Tokumi Maruyama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University,
Yamashiro-cho, Tokushima, Japan
ABSTRACT
A new method to introduce a benzyl group onto the 20-OH of purine ribonucleo-
side is described. Thus, 6-chloropurine 30-O-benzoylriboside and its 50-O-trityl
congener were condensed with benzyl alcohol using the Mitsunobu reaction to
give the 20-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depend-
ing on the solvent. The product was converted to adenosine, indicating that the
stereochemistry at C-20 is retained.
The Mitsunobu reaction is a universal method to condense the acid and alcohol
accompanied with inversion of the configuration of the alcoholic hydroxyl group.[1]
One exceptional case is a sterically hindered sugar,[2] in which resistance to SN2 dis-
placement was reported. Also, Wentwarth and Janda reported the displacement of
arabinoside to 20-O-benzylated riboside using the Mitsunobu reaction with benzyl
alcohol.[3] This method could be an alternative approach to obtain the 20-O-alkylated
*Correspondence: Tokumi Maruyama, Faculty of Pharmaceutical Sciences, Tokushima Bunri
University, Yamashiro-cho, 770-8514 Tokushima, Japan; Fax: +81 88 655 3051; E-mail:
maruyama@ph.bunri-u.ac.jp.
779
DOI: 10.1081/NCN-120022633
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

780
Kozai et al.
Chart.
ribonucleoside. However, it takes several steps to prepare arabinoside. This back-
ground prompted us to develop a method to introduce an alkyl group onto the
purine ribonucleoside.
6-Chloropurine 30-O-benzylriboside (1a) and its 50-O-trityl congener (1b) were
prepared by the method as described in an earlier report.[4] Then, compound 1b was
subjected to the reaction with benzyl alcohol (4 eq.) in the presence of N,N,N0,N0-
tetramethylazodicarboxamide [TMAD, 1,10-azobis-(N,N-dimethylformamide)][5]
and triphenylphosphine (TPP) in a solvent. The reaction was monitored by high-
performance liquid chromatography (HPLC). In a non-proton polar solvent such
as N,N-dimethyl-formamide (DMF), the peak of the 20-O-benzyl congener (2b)
appeared in low yield (4.6%). Also, a trial in tetrahydrofuran (THF) gave 2b in
14% yield. In spite of this result, a similar reaction performed in 1,4-dioxane gave
2b[6] in 45% yield. The best result was obtained when the reaction was carried out
in benzene, in which conversion was estimated to be 62.5% yield. After work-up
of the solution, 2b was obtained in 57% yield. An attempt to change TMAD to
diisopropyl azodicarboxylate (DIAD) decreased the yield of 2b to 17.7% in the
1,4-dioxane solvent system. To evaluate the role of the 50-O-protecting group, 30-O-
benzyolriboside 1a was subjected to a similar reaction to afford 2a.[7] It appeared
that the 50-O-protection did not benefit the condensation. Compound 2b was treated
with NH3 in MeOH to afford 20-O-benzyladenosine (3),[8] which showed nuclear
Overhauser effect (NOE) between H20 and H30 in the two-dimensional NOE
(NOESY) spectrum. Thus, the configuration of 3 was identified as a 2’(R)-riboside
structure.
REFERENCES
1. Mitsunobu, O. Synthesis 1981, 1–28.
2. Grynkiewicz, Rocz. Chem. 1976, 50, 1499.
3. a) Chen, Y.-C.J.; Hansske, F.; Janda, K.D.; Robins, M.J. J. Org. Chem. 1991,
56, 3410–3413; b) Wentworth, Jr. P.; Janda, K.D. J. Chem. Soc., Chem. Comm.
1996, 2097–2098.
4. Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.; Izawa, K. Chem. Pharm.
Bull. 1999, 47, 966–970.
5. Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994, 539–542.

20-O-Benzoylation of Purine Nucleoside
781
1
6. A caramel. MS m=z: 479, 481 (M+-Tr). H-NMR (600 MHz, CDCl3) d: 6.95–
7.11 (5H, m, CH2C6H5), 4.63 (1H, d, J ¼ 12.4, one of CH2C6H5), 4.45 (1H, d,
J ¼ 12.4, one of CH2C6H5).
7. White crystals. mp 167.5–169.5ꢀC. Anal Calcd for C24H21ClN4O5: C, 59.94;
H, 4.40; N, 11.65. Found: C, 59.97; H, 4.49; N, 11.60. MS m=z: 450, 452
(M+-CH2O). UV lmax (MeOH) nm: 265. 1H-NMR (600 MHz, CDCl3) d:
6.84–6.94 (5H, m, CH2C6H5), 4.55–4.57 (2H, m, H40 , one of CH2C6H5), 4.29
(1H, d, J ¼ 12.1 Hz, one of CH2C6H5).
8. Christensen, L.E.; Broom, A.D. J. Org. Chem. 1972, 37, 3398–3401.